The human major histocompatibility locus (HLA) is a complex of several linked, polymorphic genes which are structurally and functionally related and are involved in a number of aspects of immune recognition. The genes have been grouped into three classes and we propose to study the class I genes which encode the classical transplantation antigens and which are involved in allograft rejection and response to foreign antigens. There are three class I loci and we have cloned allelic genes from two of the loci, HLA-A and -B, and now wish to isolate and sequence a C locus gene. This will provide much needed biochemical and genetic information on that locus which is currently poorly characterized. We will also isolate the intergenic DNA between the B and C loci, which are very closely linked, in a search for additional MHC encoded genes. The clones will be altered by a variety of mutagenic procedures, sequenced to provide data on the mechanisms of generation of polymorphisms and a restriction endonuclease map necessary for the mutagenesis experiments. The clones for the HLA-A, -B and -C genes will be transfected and re-expressed in tissue culture cells which will be tested as targets in a variety of immune recognition systems. By making specific mutations in the protein sequence it will be possible to identify which parts of the protein are involved in recognition by alloantisera, allogeneic, killer T cells and virus-specific, HLA restricted cytotoxic T cells. In doing this, we will obtain information on the number and organization of the various immunological determinants recognized in the different systems and ultimately their role in HLA/foreign antigen/T cell receptor interactions.